Dihydrobenzothiadiazines



United Stats 3,090,783 DIHYDROBENZOTHIADIAZINES Harry L. Yale, NewBrunswick, N.J., assignor to Olin Mathieson Chemical Corporation, NewYork, N.Y., a

corporation of Virginia No Drawing. Filed June 12, 1962, Ser. No.201,811

14 Claims. (Cl. 260-243) as well as non-toxic acid addition saltsthereof, wherein R is hydrogen, lower alkyl, halo, halo(lower alkyl)such as dichlorornethyl and trifiuoromethyl, lower alkoxy, YN- sulfonyl,wherein YN is as hereinafter defined, alkyl sulfonyl, aralkyl sulfonyl,or cyano; one R is hydrogen and the other is a YN-(lower alkyl) radical,wherein YN is amino, mono(lower aikyDamino, diflower alkyl)amino,monocyclic ar( lower alkyl)arnino, or a monocyclic saturatedN-heterocyclic radical, such as piperidino, pyrrolidino, piperazino,4-(lower alkyl)piperazino, 4-(hydroxylower alkyl)-piperazino, or4-(hydroxy-lower alkoxylower alkyl)piperazino; R" is hydrogen, loweralkyl, lower halo alkyl, diaryl(alkenyl), monocyclic ar(lower alltyl),monocyclic ar(lower alkenyl), monocyclic aroyl (lower alkyl)diarylalkyl, monocyclic arylmercaptoflower alkyl, monocyclic ar(loweralkyl)mercapto-(lower alkyl, monocyclic aryloxyflower alkyl), ormonocyclic ar(lower alkoxy)lower alkyl; and R' is hydrogen or sulfarnyl.

The compounds of Formula I are physiologically active substances whichpossess central nervous system depressant activity and hence may be usedin lieu of known central nervous system depressants, such astrifiupromazine to produce ataraxis, for which purpose they areadministered orally or parenterally in the same manner astritiupromazine, with dosage adjusted for the respective activity of theparticular compound. Moreover, those final products of this inventionwhich possess a 7-sulfamyl substituent (R is sulfamyl) also possessdiuretic as well as anti-hypertensive activity and thus can beadministered parenterally and (preferably) orally in the treatment ofcongestive heart failure, being uniquely suitable for this and otherconditions where both the diuretic (i.e., naturetic) and hypotensiveactivities are desirable.

The compounds of Formula I can be prepared in a number of ways. Thus,those compounds which contain the aminoalkyl substituent in the2-position can he prepared by a series of steps, involving first thereaction of a 4,4'- di-R-2,2-dinitrodiphenylsulfide of the formulawherein R is as hereinbefore defined, with chlorine whereby thecorresponding o-nitrop-R-benzenesulfonyl chloride derivative of theformula R NO:

is formed. Among the compounds which can thus be prepared there can benamed inter alia: 4-lower alkyl-Z- nitro-benzenesulfonyl chloride, suchas 4-methyl-2-nitrobenzenesulfonyl chloride and4-ethyl-2-nitro-benzenesulfonyl chloride; 4-halo-2-nitro-benzenesulionylchlorides, such as 4-chloro and 4fluoro-2-nitro-benzenesulfonylchloride; 4-halo(lower alkyl) 2 nitrobenzenesulfonyl chlorides, such as4-trifiuoromethylbenzenesulfonyl chloride; 4-lower alkoxy 2nitro-benzenesulfonylchlorides, such as4-methoxy-2-nitro=benzenesulfonyl chloride;4-cyano-2-nitro-benzenesulfonyl chloride; 4-(YNsulfonyl)-2-nitro-benzenesulfonyl chlorides, wherein YN is as hereinbefore defined,such as 4-(N,N-diethylsulfamyl)-2-nitrobenzenesulfonyl chloride and4-(N,N-dimethylsulfamyl)- 2-nitro-benzenesulfonyl chloride; and4-[alkyl(or aralkyl)-sulfonyl]-2-nitrobenzenesulfonyl chlorides, such as4-rnesyl-2-nitro-henzenesulfonyl chloride and4-benzylsulfonyl-2-nitro-benzenesulfonyl chloride.

The benzenesulfonyl chlorides of Formula III are next converted to newintermediates of this invention, the corresponding sulfonamides of thegeneral formula -SOz-(lower alkyl) *NY wherein R and YN are ashereinbefore defined, by treatment with a YN-(lower alkyD-amine, such asan alkylenediamine, e.g., ethylenediamine and propylenediamine; andN-mono or N,N-di-lower alkyl-alkylenediamine, e.g.,N,N-dimethylethylenediamine, N,N diethyl-propylenediamine,N-methylethylencdiamine and N-ethyl-propylenediamine; an N-(rnonocyclicsaturated N-heterocyclic)alkylenediamine, e.g., Z-piperidinoethylamine,3-piperidinopropylamine; Z-pyrrolidinoethylamine;4-pyrrolidinobutylamine, piperizinomethylamine, Z-piperazinoethylamine;3-piperazinopropylamine; 2 (4 methylpiperazino)ethylamine; 3 (4ethylpiperazino)propylamine,2-[4-(fl-hydroxyethyl)-piperazino]ethylamine; and 2-[4-(fi-hydroxymethoxyethyUpiperazino]-ethylarnine; and an N-(monocyclic-ar(loweralkyiflalkylenediamine, e.g., N-benzylethylenediamine andN-phenethylpropylenediamine.

The 2-nitro-4-R-N-[YN-(lower alkyDkbenzenesulfonamides of Formula IV arethen reduced to the corresponding 2-amino-4-R-N- [YN-(lower alkyl)]-benzenesulfonamides wherein R and YN are as hereinbefore defined; andthen treated with an aldehyde of the formula RCHO to yield the2-YN(lower alkyl)-3-R"-6R-3,4-dihydrobenzothiadiazine-l,l-dioxides ofthis invention represented by the formula N- (lower allryl) -NII CIIR"wherein R, R" and YN are as hereinhetore defined.

Among the suitable aldehyde reactants may be mentioned: alkanals andhaloalkanals, particularly the lower alkanals and lower haloalkanals,such as formaldehyde, acetaldehyde, dichloroucetaldehyde,propionaldehyde, 2,

2-dichloropropionaldehyde and butyraldehyde; aralkanals, particularlymononuclear ar(lower alkanals), such as phenylacetaldehyde,m-phenylpropionaldehyde, e-phenylpropionaldehyde,B-phenyl-n-butyraldehyde, o,m, and ptolylacetaldehyde,6-phenylcaproaldehyde, and the 0,111 and p-halo (cg. chloro), nitro,amino and lower alkoxy (e.g., methoxy) derivatives thereof; aralkenals,particularly mononuclear ar(lower alkenals), such as cinnamaldehyde,,H-phcnylcrotonaldehyde, 2-phenyl-2-hexenal, and 2-phenyl-4-hexenal;aroyl alkanals, particularly mononuclear aroyl(lower alkanals), such asphenylglyoxal, flbenzoylpropionaldehyde and 'y-benzoylvaleraldehyde;diarylalkanals, particularly mononuclear diaryl-lower alkanals, such asdiphenylacctaldehyde, [i.B-diphenylprd pionaldehyde, anda,5-diphei1ylpropionaldehyde, diarylalkenals, particularly mononucleardiaryl-lower alkenals, such as {Lfi-diphenylcrotonaldehyde;aryloxyalkanals, particularly mononuclear aryloxy (lower alkanals), suchas phenoxyacetaldehyde, fl-phenoxypropionaldehyde and 7 0,111 orp-tolyloxy-n-butyraldehyde; aralkoxyallzanals, particularly mononucleararyl(lower alkoxy) (lower alkanals), such as benzyloxyacetaldehyde andfl-phcnethoxyp r o p i o naldehyde; arylmercaptoalkanals, particularlymononuclear arylrnercapto (lower alkanals), such asphenylmercaptoacetaldehyde and B-phenylmercapto propionaldehyde; andaralkylmercaptoalkanals, particularly mononuclear aryl(loweralkyl)mercapto(lower alkanals), such as benzylmercaptoacetaldehyde,fi-bcnzylmercaptopropionaldchyde and -benzylrnercapto-n-butyraldehyde.

The compounds of Formula V can be readily converted to their 7-sulfamylanalogs by chlorosulfonation (as with chlorosulfonic acid and sodiumchloride in an inert solvent) and then treatment of the resulting7-chlorosulfonyl intermediate with ammonia.

Alternatively, the 2-nitro-4-R'-N-[YN-(lower alkyl)]benzene-sulfonamides of Formula IV may be reduced to the corresponding2-amino 4-R'-n-[YN-(lower alkyl)] benzenesulfonamides wherein R and YNare as hereinbefore defined; and then treated with formic acid; an orthoester, i.e., R"C(O-lower alkyl);,; or an acid chloride, i.e., R"COCl, toyield the 2(YN-lower alkyl-3-R"- 6-R'-1,2,4-benzothiadiazine of thisinvention represented by the formula C RII wherein R, R and YN are ashereinbefore defined. Among the suitable reagents may be mentioned:formic acid, lower alkanoic acid chlorides and lower alkylorthoalkanoates, such as acetyl chloride, propionyl chloride, butyrylchloride, ethyl orthoacetate and ethylorthopropionate; aralkanoylchlorides and lower alkyl orthoaralkanoic acid esters particularlymononuclear aralkanoyl chlorides and lower alkyl ortho ar(loweralkanoic) esters such as phenylacetyl chloride, ethylorthophcnylacetate, a-phenylpropionyl chloride, ethylortho-propionate,ethyl ortho-B-phenylpropionate, B-phenyl-n-butyryl chloride, o,n1 andp-tolylacctyl chloride, 6-phenylcaproyl chloride and the cm and phalo(e.g., chloro), nitro-, amino-, and lower alkoxy (e.g. methoxy)derivatives thereof; orthoaralkenoic esters and aralkenoyl chlorides,particularly mononuclear ar(lower alkenoyl)chlorides and alkyl orthoar(lower alkenoic) esters such as cinamyl chloride, phenyl-crotonylchloride, ethyl ortho 2-phenyl-2-hexenoate and ethyl ortho2-phenyl-4-hexenoate alkyl; ortho aroylalkanoates and aroylalkanoylchlorides particularly lower alkyl ortho mononuclear aroyl(loweralkanoic)esters and aroyl( lower alkanoyl)chlorides such as ethyl orthophenyl oxalate, fl-benzoylpropionyl chloride and 'y-benzoylvaleroylchloride; diaryl alkcnoylchlorides and ortho esters, particularlymononuclear diaryl(lower alkanoyl) chlorides and ortho esters such sdiphenylacetyl chloride, pLB-diphenylpropionyl chloride and ethyl orthou,fl-diphenylpropionic ester; diaryl alkenoic ortho esters and acidchlorides, particularly mononuclear ethyl ortho diaryl(lower alkenoic)esters and diaryl (lower alkanoyl) chlorides such as ethyl ortho;3,fidiphcnyl-crotonic ester; ortho aryloxy-alkyl esters andaryloxyalkanoyl chlorides, particularly mononuclear aryloxy (loweralkanoyl) chlorides and ortho esters such as phenoxyacetyl chloride,ethyl ortho B-phenoxypropionyl ester and ethyl ortho 'y- (o,m orp-tolyoXy)-n-butyric ester; aralkoxyalkanoyl chlorides and alkyl orthoaralkoxyalkanoates, particularly rnononuclcar ethyl ortho aryl(lowcrallcoxy)-(lower alkanoates) and aryl(lowcr alkoxy)-lower alkanoylchlorides such as ethyl ortho phenethoxy acetate and ethyl orthobenzyloxyacetate; arylmercaptoalkanoyl chlorides and orthoarylmercaptoalkanoic esters, particularly mononucleararylmercapto-(lower alkanoyl) chlorides and ethyl orthoarylmercaptoflower alkanoic) esters such as ethyl orthophenylmercaptoacetate and [S-phenylmercaptopropionyl chloride; andaralkylrnercaptoalkanoyl chlorides and alkyl ortho-aralkylmercaptoalkanoic esters, particularly mononuclear ar lower alkyl)mercapto loweralkanoyl chlorides and ethyl ortho-aryl(lower allryUmercaptodoweralkanoates such as ethyl ortho benzylrnercaptoacetate,,B-phenethylrnercaptopropionyl chloride and ethyl ortho'y-benzylrnercapto-n-butyric ester.

The compounds of Formula VI can be readily converted to thecorresponding 7-sulfamyl derivatives by chlorosult'onation (as withsulfonyl chloride and sodium chloride in an inert solvent) and thentreatment of the resulting 7-chlorosulfonyl intermediate with ammonia.

The 4-YN(lower alkyl)-3-R" 6-R-7-R'-3,4-dihydro-l,2,4-benzothiadiazine-Ll-dioxides of Formula I are prepared by analternative process which comprises heating a2-arnino-4-R-benzcnesultonamide of the formula:

VII wherein R is as hereinbefore defined, with formic acid an orthoester, i.e., RC(O-lower alkyl) or an acid chloride, i.e., R"COC1reagent, thereby forming a 3-R"-6R- benzothiadiazine-l,l-dioxide of theformula:

VIII

wherein R and R" are as hereinbefore defined.

Among the suitable reagents may be mentioned: formic acid, loweralkanoic acid chlorides or lower alkyl orthoalkanoates, such as acetylchloride, propionyl chloride, butyryl chloride, ethyl orthoacetate andcthylorthopropionate; aralkanoyl chlorides and lower alkylorthoaralkanoic acid esters particularly mononuclear aralkanoylchlorides and lower alltyl ortho ar(lower alkanoic) esters, such asphenylacctyl chloride, ethyl orthophenylacetate, a-phcnylpropionylchloride, ethylorthopropionate, ethyl ortho-B-phenylpropionate,fi-phcnyl-n-butyryl chloride, o,n1 and p-tolyl-acetyl chloride,o-phenyl-caproyl chloride and the o,m and p-halo- (e.g., chloro),nitro-, amino-, and lower alkoxy (e.g., methoxy) derivatives thereof,orthoaralkenoic esters and arallrenoyl chlorides, particularlyrnononuclear ar(lower alkenoyl) chlorides and alkyl ortho ar (loweralkenoic) esters such as cinnamyl chloride, fi-phenyl-erotonyl chloride,ethyl ortho 2- phenyl-Z-hexenoate and ethyl ortho Lphenyl-thexenoatealkyl; lower alkyl ortho aroyl(lower alkanoates) and aroyl (loweralltanoyl) chlorides, particularly lower alkyl mononuclear ortho aroyl(lower alkanoic) esters and aroyl (lower alkanoyl) chlorides such asethyl ortho phenyloxalate, fl-benzoylpropionyl chloride and'y-henzoylvaleroyl chloride; diaryl alkanoyl chlorides and ortho esters,particularly mononuclear diaryl(lower alkanoyl) chlorides and orthoesters, such as diphenylacetyl chloride, 8,;3-diphenylpropionyl chlorideand ethyl ortho 11,,8- diphenyl propionate; ortho diaryl alkenoic estersand acid chlorides, particularly mononuelear lower alkyl orthodiaryl(lower alkenoic) esters and diaryl (lower alkenoyl) chlorides,such as ethyl ortho fLfi-diphenyl crotonic ester; ortho aryloxyalkylesters and aryloxyalkanoyl chlorides, particularly mononuclear aryloxy(lower alkanoyl) chlorides and ortho esters, such as phenoxyacetylchloride, ethyl ortho fl-phenoxypropionyl ester and ethyl ortho 'y- (o,m or p-tolyoxy)-n-butyric ester; aralkoxy-alkanoyl chlorides and alkylortho aralkoxyalkanoates particularly mononuclear ethyl ortho aryl(lowcralkoxy)-(lower alkanoates) and aryl (lower alkoxy)-lower alkanoylchlorides, such as ethyl ortho phenethoxy acetate and ethyl orthobenzyloxyacetate; arylmercaptoalkanoyl chlorides and orthoarylmercaptoalkanoic esters, particularly mononucleararylmercapto-(lower alkanoyl) chlorides and lower alkyl orthoarylmercapto (lower alkanoic) esters such as ethyl orthophenylmercaptoacetate and ti-phenylmercaptopropionyl chloride; andaralkylmercaptoalkanoyl chlorides and alkylortho-aralkylmercaptoalkanoic esters, particularly mononuclear ar(loweralkyDrnercapto lower alkanoyl chlorides and ethyl ortho-aryl-(loweralltyl)mercapto-lower alkanoates, such as ethyl orthobenzylmercaptoacetate, ,B-phenethylmercaptopropionyl chloride and ethylortho- -benzylmercapto-n-butyric ester.

Among the suitable benzene sulfonamide reagents, there may be namedinter alia: 2-aminobenzenesulfonamide; 4-loweralkyl-Z-aminobenzenesulfonamides, such as4-methyl-2-aminobcnzenesulfonamide, 4-ethyl-2-aminobenzenesulfonamideand 4-propyl-2-atninobenzenesulfonamide;4-hal0-2-arninobenzenesulfonamides, such as 4-chloro2-aminobenzenesulfonamide and 4-fluoro-2-amino benzenesulfonamide;4 haloalkyl-2-aminobenzenesulfonamides, particularly 4-halo(loweraIkyD-Z-aminobenzene sulfonamides, such as4-triliuoromethyl-2-aminobenzcnesulfonamide, 4-dichloromethyl 2aminobenzenesulfonamide and4-[3,Q-dichloro-ethyl2-aminobenzenesulfonamide;4-alkoxy-2-amino-benzcnesulfonamides particularly 4-(loweralkoxy)-2-an1inobenzenesulfonamides, such as4-rnethoxy-Z-aminobenzenesulfonamide; 4-cyano-2-aminobenzenesulfonamide;4-YN-sulfamyl-2-aminobenzenesulfonamides, wherein YN is as hereinheforedefined, such as N,N-dimethylsulfamyl-Z-aminobenzenesulfonamide; 4-alkanesulfonyl-2-aminobenzencsulfonamides, particularly 4-(lower alkane}sulfonyl 2-aminobenzenesulfonamides, such as4-mesyI-Z-aminobenzenesulfonamide; and 4-aralkanesulfonyl-2-aminobenzenesulfonamides.

The benzothiadiazine-l,l-dioxides of Formula VIII are next converted tothe 4-YN(lower alkyl)-derivatives of the formula:

II R /C R N (lliwer alkyl) wherein R, R" and YN are as hereinbeforedefined, as by treatment with sodamide and an aminoalkyl chloride of theformula YN-(lower aIkyDchloride. Among the suitable amino compoundsthere may be named: aminoalkyl chlorides (branched or straight chained),such as 2-chloro-ethylamine, 3-chloro-propylamine, and-chloro-hexylamine; N-substituted-arnino-alkyl chlorides, such asN-rnethyl-Z-chloro-ethylarnine and N,N-diethyl-2- chloroethylamine;N-heterocyclic alkyl chlorides, such as piperidinoethyl chloride,Z-piperidinopropyl chloride, 3-

piperidinopropyl chloride, Z-pyrrolidinoethyl chloride, 5-pyrrolidinohexyl chloride, piperazinomethyl chloride, 2- piperazinoethylchloride, 3-piperazinopropyl chloride, 2- (4-methylpiperazino) ethylchloride, 3-(4-ethylpiperazino) propyl chloride,2-(4-hydroxyethylpiperazino)ethyl chloride,2-(4hydroxymethoxypiperazino)ethyl chloride, and 3 {4(5hydroxyethoxyethylpiperazino)propyl chloride; and N-[monocyclic-ar(loweralkyl)] chloroalkylamines, such as N-benzyl-Z-chloro ethylamine andN'phenethyl- 3-chloro-propylamine.

Compounds of Formula IX are then reduced as by treatment with lithiumaluminum hydride and aluminum chloride, to yield the 4-YN(loweralkyl)-3-R"-6-R7-R"'- dihydrobenzothiadiazine-l,l-dioxides of theformula:

R llE-R" (lower alkyl) -N Y wherein R, R" and YN are as hereinbeforedefined.

The compounds of Formula X can be converted to their 7-sulfarnyl analogsby chlorosulfonation (as by treatment with chlorosulfonic acid andsodium chloride in an inert solvent) and then treatment of the resulting7- chloro sulfonyl intermediate with ammonia.

The compounds of this invention within the scope of Formula I are basicsubstances which react with molar amounts of acids to form salts. Thesalt forming reaction is conducted using conventional procedures.Suitable salt forming acids include non-toxic acids, such as mineralacids (e.g., hydrochloric, sulfuric, nitric and perchloric acid) andorganic acids (e.g., pamoic, tartaric, mal-eic, acetic, enanthic andsuccinic acid).

The following examples are presented to more fully illustrate thepresent invention.

EXAMPLE 1 2 (3 Dimethylaminopropyl) 6 Trifluoromethyl-1,2,4-Benzothiadiazine-1,I-Dioxide A. Preparation of2-nitr0-4-trifltzoromethyl-benzenesuIf0nyIchl0ride.-A stirred suspensionof 204 g. of crude 4,4bis(trifiuoromethyl)-2,2'-dinitrodiphenyldisulfide in 900 ml. of aceticacid is diffused with chlorine gas for a total of six hours. During thefirst four hours, the exothermic reaction is maintained at about 40 byregulating the input of chlorine; during the next two and onehalf hours,the temperature is allowed to drop slowly. The mixture is then diffusedwith nitrogen for ten minutes, filtered off from about 20 g. ofinorganic material, and the filtrate concentrated to dryness in vacuo.The residual semi-solid mass is extracted with 250 ml. of dry toluene,filtered from some insoluble material, and the filtrate concentrated invacuo. The residue is again extracted with 250 m1. of dry toluene, thesolution treated with Darco, filtered, and the filtrate concentrated invacuo to give about 209 g. of crude sulfonyl chloride as an ambercolored oil which crystallizes partially when stored in a cold room.This material is used in part B without further purification.

B. Preparation of N(3-dimerhylaminopropyl)-2-nitro-4-(trifluor0merhyl)benzenesuIjonamide.-To 48 g. of the crude sulfonylchloride of part A in 500 ml. of dry :acetonitrile, with stirring, isadded dropwise 16.3 g. of 3- dimethylaminopropylamine in 200 cc. of dryacetonitrile. The mixture i then stirred and refluxed for one hour. Theacetonitrile is distilled and the solid residue stirred with a solutionof 8.4 g. of sodium bicarbonate in 200 ml. of Water. The oil whichseparates, solidifies and is then filtered and air-dried to give 54 g.of solid which is extracted with 1600 ml. of boiling hexane (an orangegum remains) to give 37 g. of product, M.P. about 7 80-81", which isrecrystallized twice from hexane to give a product, Ml. about 8283.

C. Preparation of N (3 dimerizylnnzinopmpyi)-2-amin-4-(triflnoromerliyl)benzenesnIf0nmnide.-1t) gms. of the nitrocompound of part B in 200 ml. of 95% ethanol and 1 g. of Pd on carbon isreduced under 50 p.s.i. of hydrogen. Reduction is rapid. The mixture isfiltered and the filtrate concentrated on the steam bath. Darkening ofthe original pale yellow solution to orange occurs during thisdistillation. The residual orange oil crystallizes upon scratching andcooling. Extraction with ligroin gives 7 g. of theN-(3-dimethylaminopropyl)-2- amino 4 (trifiuoromethyl)benzenesulfo-namide which upon being recrystallized again from ligroinmelts at about 91-92".

D. Preparation of 2-(dimethyIaminopropyi)-6-trifln0- romethyl-I,2,4-benzlhindiazine-I,1-dio.ride.7 g. of the amino compound of part C and 70 ml.of triethyl orthoformate are placed in an oil bath preheated to about120 and heated at this temperature for about 2.5 hours. The excesstriethyl orthofiormate is distilled, the residual solid is trituratedwith 50 ml. of 5% aqueous sodium hydroxide, the solid filtered, washedwith water, dried, dissolved in 250 ml. of ligroine, the ligroinesolution is decolorized with carbon, filtered, and the filtrateconcentrated to give about 6.9 g. 2(dirnethylaminopropyl)-6-trifiuoromethyl-l,2,4-benzothiadiazine-l,l-dioxide, MP. about 5355.

EXAMPLE 2 2 (3 Dimethyiaminopropyl)-6-Triflnoromethyl-3,4- Dihydro-I,2,4Benz0zhiadinzine-l,1 -Di0xide A solution of 5.25 g. ofN-(3dimetbylaminopropyl)-2- amino-4-(trifluoromethyl)benzenesulfonamideobtained in Example 1, part C, 1.3 g. of 37% aqueous formaldehyde, ml.of 10% aqueous hydrochloric acid and 100 ml. of 95% ethanol is refluxedfor three hours and concentrated to dryness. The residual solid is takenup in 100 ml. of water and neutralized by the addition of dilute aqueousammonia. The precipitated solid is filtered and recrystallized fromhexane to give about 2.2 g. of 2-(3dimethylaminopropyl) 6(trifluorometbyl)-3,4-dihydro- 1,2,4-benzothiadiazine-l,l-clioxide, MP.about 122-124.

EXAMPLE 3 2 Aminoethyl 6 Trifltioromethyl-7-SnIfamyl-l,2,4-Benzothiadiazine-I ,1 -Di0xide A. Preparation ofN-(ZaminOethyI)-2-nitr0-4-Triflu0 romethylbenzcnesulfonnmide.-T0 28.9 g.of the sultonyl chloride of Example 1(A) in 509 ml. of dry acetonitrile,with stirring, is added, dropwise, 19.0 g. of Z-phthalimidoethylamine in50 .ml. of acetonitrile. Treatment in accordance with the procedure ofExample 1(B) yields a solid material which upon recrystallization issubstantially pure N (Z-phthalimidoethyD-Z-nitrot--trifiuoro methylbenzenesulfonamidc. The phthalirnido compound, 22.2 6.7 ml. 85%hydrazine hydrate and 200 ml. of 95% ethanol are refluxed for two hours,a solution of 6.5 g. of 85% potassium hydroxide in 159 ml. 95% ethanoladded, the mixture refluxed one hour, concentrated to dryness, and theresidue dissolved in water. The aqueous solution is saturated withcarbon dioxide and the precipitated solid filtered. Recrystallizationfrom hexane givesN-(Z-aminoethyl)-2-nitro-4-triiluoromethylbenzenesulfonamide.

B. Preparation t0 N-(Z-nminoerhyi)-2-amin0-4-trifln0-romerhylbcnzenesulfonamz'de.Following the procedure of Example 1(C), 10g. of the product of Example 3(A) is reduced with 5% palladium on carbonunder 50 p.s.i. of hydrogen to yield the product N-(2-aminoethyl)-2-amino-4-trifluoro methyl-benzencsulfonamide.

C. Preparation of 2 (aminoctliyl)o-triflnoromethyl-1.2,4-benzothimliazinc-I,1-di0.ridc.--A solution of 7.1 g. of theproduct of Example 3 in 70 ml. of 98% formic 8 acid is sealed in acarius tube and heated four hours at 140 and then concentrated todryness to yield Z-(aminoethyl)-6-trifiuoromethyl 1,2,4benaothiadiazine-Ll-dioxide.

D. Preparation of Z-(nminoethyi)-6-trifln0r0methyl-7-snIfcnnyi-I,2,4-bcnzor/zindiazine-I,1-di0xide.To 29.4 g. of the productof Example 3(C) in 100 ml. of tetrachloroethane is added 26 g. ofchlorosulfonic acid, dropwise. Subsequently, 11.8 g. of sodium chlorideis added in small portions. When the evolution of gas subsides, themixture is gradually raised to reflux temperature and the mixturerefluxed for two hours when HCl evolution has ceased. The mixture iscooled and added rapidly to ml. of concentrated aqueous ammonia withexternal ice cooling. Finally, the mixture is heated for two hours onthe steam bath allowing the volatile material to escape. The solid whichseparates is filtered, washed well with Water and recrystallized from50% aqueous alcohol to give2-(aminoethyl)-6-trifluorornethyl-7-sulfamyl-l ,2,4-benzothiadiazinell--dioxide.

EXAMPLE 4 Z-Armnoethyl-zi-Trifinoromethyl-7-Snlfamyl-3,4-Dihydro-I,2,4-Benzothiadiazine-l ,I-Dioxide Following the procedure ofExample 2, 7.1 g. of the N- (2 aminoethyl) 2 amino 4trifluoromethyl-benzenesulfonamide. obtained in Example 3(B) is reactedwith 2.1 g. of 37% aqueous formaldehyde in aqueous alcoholichydrochloric acid to yield2-amino-6-trifiuoromethyl-3,4-dihydro-l,2,4-benzothiadiazine-1,l-dioxide.

The 2-aminoethyl-6-trifluoromethyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is readily converted to its sulfamylderivative by treatment with chlorosulfonie acid and sodium chloride intetrachloroethane and by ammoniation, in accordance with the procedureof Example 3(D).

EXAMPLE 5 2- 5 --D iezh yiam inopentyl -6-Cl1l0r0-3-Merh yl-I ,2 ,4-Benzorlriadiazin e-],l-Di0xide A. Preparation of 4 chloro 2nilrobenzenesulfonyl chloridc.--Following the procedure of Example 1(A)except for the use, as starting material, of 188.5 g. of4,4-dichloro-2,2'-(dinitro)-diphenyldisulfide, there is obtained2-nitro-4-chloro-benzenesulfonylchloride.

B. Preparation of N-(S-diethylaminopentyl)-2-nitr0-4-chioro-benzenesulfonamide.-Following the procedure of Example 1(B)except for the use, as starting material the sulfonyl chloride of part Aand 5-diethylaminopentylamine in place of the3-dimethylarninopropylamine, there is obtained as productN(5-diethylaminopentyl)- 2-nitro-4-chlorobenzenesulfonamide.

C. Preparation of N(5-diethy[aminopentyl)-2-amin0-4-chlorobenzenesnlfonamide.-Following the procedure of Example 1(C),except for the substitution of 6.5 g. of the sulfonamide of part B asstarting material in the hydrogenation process, there is obtainedN(5-diethy1- aminopentyl) -2-amino-4-chlorobenzenesulfonarnide.

D. Preparation of 2-(S-dierhylamin pcntyl)-3-methyl-6-cltior0-1,2,4-benzothiadiazine-JJ-di0xicie.Twenty ml. oftriethylcrthoacetate are reacted with the product of part C (followingthe procedure outlined in Example 1(D)) to yield2-(S-diethylaminopentyl)-3-methyl-6-chloro-l,2,4-benzothiadiazinc-l,l-dioxide.

The product of part D is readily converted to its 7- sulfamyl derivativeby treatment with chlorosulfonic acid and sodium chloride intetrachloroethane and by amr3noni)ation, in accordance with theprocedure of Example EXAMPLE 6 2 (5-Dielhylaminopentyl)-6-ChIor-3-Merhyl-3,4- Diizydro-I,2,4-Benz0rhindiazine-I,I-Dioxide 0.88 g. ofacetaldehyde in 50 ml. of ethanol and 5 ml.

of 10% aqueous hydrochloric acid are reacted with 7.0 g. of theN-(S-diethylaminopentyl)-2-amino4-chloro benzenesulfonamide, obtained inExample (C), in a sealed carius tube to yield2-(5diethylarninopentyl)-3-methyl- 6 chloro 3,4 dihydro 1,2,4benzothiadiazine 1,1- dioxide.

The 2 (5 diethylaminopentyl) 3 methyl 6 chloro 3,4 dihydro 1,2,4benzothiadiazine 1,1 dioxide is readily converted to its 7-sulfamylderivative by treat ment with chlorosulfonic acid and sodium chloride intetrachloroethane and then ammoniation in accordance with the procedureof Example 3 (D).

EXAMPLE 7 Z-(Z-Piperidino-ethyl -3-Benzyl-6-Cyctn0-1 ,2,4- Benzothiadz'azine-I ,1 -D ioxr'de 24.7 g. of 2-nitro-4-cyanohenzenesulfonylchloride (prepared from4,4-(dicyano)-2,2-(dinitro)-diphenyldisulfide according to the procedureof Example 1(A) are reacted with 12.8 g. of 2-piperidinoethylamine inaccordance with the procedure of Example 1(B) to yield N-2-(piperidinoethyl) 2 nitro 4 cyanobenzenesulfonamide which latter isreduced in accordance with Example 1(0) to the correspondingN-(piperidinoethyl)-2-amino-4- cyanobenzenesulfonamide which is thenreacted with triethyl orthophenylacetate to yield the product2-(2-piperidinoethyl) 3 benzyl 6 cyano 1,2,4benzothiadiazine-1,l-dioxide.

The corresponding 7-sultamyl derivative is obtained by treatment withchlorosulfonic acid and sodium chloride in tetrachloroethane and thenammoniation in accordance with the procedure of Example 3(D).

EXAMPLE 8Z-(Z-Piperidinoethyl)-3-Benzyl-6-Cyano-3,4-Diliydro-I,2,4-Benz0thiadiazine-],1-Di0xide24.7 g. of 2-nitro-4-cyano benzenesulfonylchloride (prepared from4,4-(dicyano)-2,2'-(dinitro)-diphenyldisulfide according to theprocedure of Example 1(A) are reacted with 12.8 g. ofZ-piperidinoethylamine in accordance with the procedure of Example 1(B)to yield N-(2- piperidinoethyl) 2 nitro 4 cyanobenzenesulfonamide whichlatter is reduced as in accordance with Example 1(C) to thecorresponding N-(piperidinoethyl)-2-arnino- 4-cyanobenzenesulfonamidewhich is then reacted with phenylacetaldehyde to yield the product2-(2-piperidinoethyl) 3 benzyl 6 cyano 3,4 dihydro 1,2,4-benzothiadiazine-1,1-dioxide.

The corresponding 7-sulfamyl derivative is obtained by treatment withchlorosulfonic acid and sodium chloride in tetrachloroethane and thenammoniation in accordance with the procedure of Example 3(D).

EXAMPLE 9 2- [3- (4-Methylpiperazino Propyl] -3 (a-Methylbenzyl)6-Meti2oxy-1 ,2,4-Benz0!hiadiazine-I ,1 -D ioxide 25.2 g. of4-rnethoxy-2-nitro benzenesulfonylchloride (prepared in accordance withthe procedure of Example 1(A) from4,4'-dirnethoxy-2,2'-dinitro-diphenyldisulfide) are reacted with 15.7 g.of 3-(4-rnethylpiperazino)-propylamine to yieldN-[3-(4-methylpiperazino)propyl}-2- nitro-4-methoxy-benzenesulfonamidewhich latter is hydrogenated in accordance with the procedure of Example1(C) to yield the N-[3-(4-methylpiperazino)propyl]-2- amino 4methoxybenzenesulfonamide. The latter is treated withtriethylortho-(a-methylbenzylformate) in accordance with the procedureof Example 1(D) thereby yielding the product2[3-(4-methyipiperazine)propyl] 3(m methylbenzyl) 6 methoxy 1,2,4benzothiadiazine-1,1-dioxide.

The corresponding 7-sulfamyl derivative thereof is readily obtained bytreatment with chlorosulfonic acid and sodium chloride intetrachloroethane and then am- 10 moniation in accordance with theprocedure of Example 3(D).

EXAMPLE l0 2-[3-(4-Merhylpipcrazino)Propyl]-3-(a MethylbenzyD-6Me!h0xy-3,4-Dihydr0 1,2,4 Benzothiadiazine-LI- Dioxide 25.2 g. of4-methoxy-2-nitro benzenesulfonylchloride (prepared in accordance withthe procedure of Example 1(A) from 4,4'-dimethoxy 2,2dinitrophenyldisulfide) are reacted with 15.7 g. of3-(4-methylpiperazino)-propylamine to yieldN-{3-(4-methylpiperazino)propyH-Z-nitro- 4-rnethoxy-benzenesulfonamidewhich latter is hydrogenated in accordance with the procedure of Example1(C) to yield N-(3-(4-methylpiperazino)propyl 2 amino-4-methoxy-benzenesulfonamide. The latter is treated with2-methyl-2-phenyl-aceta1dehyde in accordance with the procedure ofExample 2 thereby yielding the product 2-[3-(4methylpiperazino)propyl]-3 (a-methyl-benzyD- 6-methoxy 3,4 dihydro 1,2,4benzothiadiazine-1,1- dioxide.

The corresponding 7-sulfamyl derivative thereof is readily obtained bytreatment with chlorosulfonic acid and sodium chloride intetrachloroethane and then ammoniation in accordance with the procedureof Example 3(D).

EXAMPLE 11 2 [3 (4Hydroxyethylpiperazino)Propyl]-3-Phenoxymethyl-6-TrifluoromethyI-1,2,4-Benzorhiadiazine1,1- Dioxide Following the procedure of Example 1, parts B, C and D,there are respectively preparedN-[3-(4-hydroxyethylpiperazino)-pr0pyl]-2nitro 4trifluorornethyl-benzenesulfonamide, 2amino-N-[3-(4-hydroxyethylpiperazino)propyl]-4-trifluoromethyl-benzenesulfonamide and the latter, treatedwith triethyl orthophenoxyacetate to give the product2-13-(4-hydroxyethylpiperazino)propyl] 3phenoxyrnethyl-G-trifluoromethyl-1,2,4-benzothiadiazine 1,1-

dioxide. The corresponding 7-sulfamyl derivative is readily prepared bytreatment of the latter with chlorosulfonic acid and sodium chloride intetrachloroethane and then ammoniation in accordance with Example 3(D).

EXAMPLE l2 2 [3 (4Hydroxyelhyt'piperazino)Propylj-3Phen0xymethyl-6-Triflu0r0methyl3,4-Dihydro-I,2,4-BenzothiadiazineJ, 1 -Dz'0xide Following the procedureof Example 1, parts B and C, there are respectively preparedN-[3-(4-hydroxyethylpiperazino)propyl]-2-nitro 4trifluoromethyl-benzenesulfonamide, 2amino-N-[3-(4-hydroxyethylpiperazino) propyl] 4trifiuoromethyl-benzenesulfonamide and then following the procedure ofExample 2, there is obtained the product2-[3-(4-hydroxyethylpiperazino)propyl]-3-phenoxymethyl--trifiuorornethyl 3,4 dihydro 1,2,4-benzothiadiazine-1,1-dioxide. The corresponding 7-sulfamyl derivative isreadily prepared by treatment of the latter with chlorosulfonic acid andsodium chloride in tetrachloroethane and then ammoniation in accordancewith Example 3(D).

EXAMPLE 13 2 (3Pyrrolidl'nopmpyl)-6-Methoxy-3-PhenylmercaptomethyI-3,4-1,2,4-Benz0thiaa'iazine-J,1 -Dioxide A. Preparation of 4-mct/zoxy-2-nitrobenzenesulfonylchloride.Following the procedure of Example 1(A) exceptfor the use of, as starting material, 41.6 g. of 4,4- dirnethoxy 2,2dinitro, diphenyldisulffide, there is obtained2-nitro-4-methoxybenzenesulfonylchloride.

B. Preparation of N-pyrrolidinopropyl 2nitro-4-metlzoxy--benzenesulfonamide.Following the procedure of Example1(B) except for the use of, as starting material, 15.0 g. of thesulfonyl chloride and 6.2 g. of S-(N-pyrrolidino)propylamine of part A,there is obtained as product, N-(pyrrolidinopropyl)-2-nitr0 4-methoxy-benzenesulfonamide.

C. Preparation ofN-pyrroh'dinopropyl-Zumin0-4-methoxy-benzenesulfonamide.Following thehydrogenation procedure of Example 1(C) except for the use of 6.2 g. ofthe sulfonamide of part B as starting material, there is obtainedN-pyrrolidinopropyl-Z-aminoA-methoxy-benzenesulfonamide.

D. Preparation of 2-pyrrolidinopropyl 3phenylmercaptomethyl-G-methoxy-I,2,4benzothz'adr'azirze-I,1dioxidc.Sodium thiophenylate andchloroacetonitrile are reacted in refluxing ethanol to givephenylmercaptoacetonitrile. The phenylmereaptoacetonitrile in absoluteethanol is treated with dry hydrogen chloride at until the mixture issaturated, then set aside in the cold for two days. Addition of fivevolumes of anhydrous ether precipitates the imido ester hydrochloride,which is filtered, redissolved in absolute ethanol and the solutionrefluxed to give triethyl orthophenylmercaptoacetate.

5.4 g. of triethyl orthophenylmercaptoacetate are reacted with theproduct of part C, following the procedure of Example 1(D), to yieldZ-pyrrolidinopropyl-3-phenylmercaptomethyl-G-methoxy 1,2,4benzothiadiazine-Lldioxide.

The product of part D is readily converted to its 7-sulfamyl derivativeby treatment with sulfonyl chloride and sodium chloride in ethylenedichloride, and then ammoniation in accordance with the procedure ofExample 3(D).

EXAMPLE l4 2-(3-Pyrr0lidin0propyl)-6-Methoxy 3Plienylmercnptomethyl-3,4-Dihydra-I,2,4-Benz0thindiazine-IJ-Dioxide 15.2g. of phenylmercaptoacetaldehyde are reacted with 30.9 g. of theN-pyrrolidinopropyl-2-amino-4-methoxy-benzeneslfonamide, obtained inExample 13, part C, following the procedure of Example 2, to yieldZ-pyrrolidinopropyl-3-phenylmercaptomethyl 6 methoxy-3,4-dihydro-1,2,4-benzothiadiazine-l,l-dioxide.

The product of Example 14 is readily converted to its 7-sulfamy1derivative by treatment With chlorosulfonic acid and sodium chloride inethylene dichloride, and then ammoniation in accordance with theprocedure of Example 3(D).

EXAMPLE 15 4-Aminoethyl-o-Trijluoromethyl-l ,2,4-Bcnzolhiadiazine-1,1-Di0xide A. Preparation of d-trifluoromethyl 1,2,4-benzothiadiazine-I,I di0xia'e.2-nitro 4 trifiuoromethylbenzenesulfonylchloride prepared as in Example 1(A) is reacted with concentratedaqueous ammonia to give 2-nitro-4- trifiuoromethylbenzenesulfonamide,M.P. 16ll63 after recrystallization from 50% aqueous ispropanol.Reduction of the nitro compound in ethanol, using 5% palladiurn oncarbon under 50 p.s.i. of hydrogen and at 50 give2-amino-4-trifluoromethylbenzenesulfonamide, M.P. 148l49. The aminocompound and four volumes of 98100% formic acid are refluxed for twohours and the solution concentrated to dryness to givefi-trifiuoromethyl- 1,2,4-benzothiadiazine-1,1-dioxide, Ml. 253255 afterrecrystallization from water.

B. Preparation of 4 amz'noetlzyl 6 lrifluoromct/zyl-I,2,4-benz0thiadiazine-I,1-di0xide.--A mixture of 23.5 g. of the productfrom 4.7 g. of sodium amide and 200 ml. of dry dimethyl ether ofdiethylene glycol are stirred for one hour at room temperature and then30.4 g. of 2-phalimidoethyl bromide in 50 ml. of the same solvent isndded, dropwise. The mixture is stirred and heated at 110 for 24 hours,filtered, and the filtrate concentrated to dryness. The residue isdissolved in 500 ml. of 95% ethanol, 6.7 ml. of 85% hydrazine hydrateadded and the solution is refluxed for four hours, cooled, 6.7 g. of 85%potassium hydroxide is added, re

12 fluxing continued for one hour, and the solution concentrated todryness. The residue is dissolved in water and the solution is saturatedwith carbon dioxide. The oil which separates is extracted withchloroform, the chloroform extracts are dried and concentrated to give4-aminoethyl-fi-trifluoromethyl 1,2,4 benzothiadiazine- 1,1-dioxide.

EXAMPLE l6 4-Aminoethyl-d-Triflzroromerizyl-SA-Dihydro-I,2,4Benzothiadiazine-I ,I-Dioxide The 4-aminoethyl 6trifluoromethyl-l,2,4-benzothiadiazine-1,l-dioxide, obtained in Example15, part B, is reduced by means of a mixture of lithium aluminum hydrideand aluminum chloride (1:1 molar ratio) to give 4 aminoethyl 6trifluoromethyl 3,4 dihydro-l,2,4- benzothiudiazine-l,l-dioxide.

EXAMPLE 17 4 [5- (N,N-Diczhylamin0) Pentyl] -3-Methyl-6-Chl0r0-1,2,4-Benz0thiadiazine-l ,J-Dioxide Reaction of 20.6 g. of4-chloro-2-aminobenzenesulfonamide with 40 ml. of triethyl orthoaeetatein accordance with the procedure outlined in Example 15(A) yields6--chloro-3-methyl-l,2,4-benzothiadiazine-1,1-dioxide. Reaction of 21.4g. of the latter with 21.3 g. of N,N-di ethyl-l-aminopentyl chloride and4.7 g. of sodamide in accordance with the procedure of Example 15(B)yields the product 3 methyl 4[N,N-diethylaminopentyl]-6-chloro-1,2,4-benzothiadiazine-l,1-dioxide.

The corresponding 7-sulfamyl derivative is readily prepared inaccordance with the procedure of Example 3(D) by chlorosulfonation, andthen ammoniation of the thus obtained 7-sulfonylchloride derivative.

EXAMPLE l8 The 3-methyl-4-(N,N diethylaminopentyl)-6-chloro-1,2,4-benzothiadiazine-1,1-dioxide, obtained in Example 17, is reducedwith lithium aluminum hydride and aluminum chloride to yield the desiredproduct 3-methyl- 4-[5-(N,N-diethylamino)-pentyl] 6chloro-3,4-dihydrol,2,4-benzothiadiazine-1,l-dioxide The corresponding7-sulfamyl derivative is readily prepared in accordance with theprocedure of Example 3(D) by chlorosulfonation, and then ammoniation ofthe thus obtained 7-sulfonylchloride derivative.

EXAMPLE l9 4- [2-(Piperidin0)Erhyl] 3-BenzyI-6-Met/10xy-1,2,4-Bcnzothiodiazine-l ,I-Dioxide EXAMPLE 20 4-[Z-(Piperidino)Ethyl]-3-Benzyl-6-Methway-3,4-Di/tydro-l,2,4-Bcnzothiadiazine-I,I-Di0xidc The 3benzyl-4-[Z-piperidinoethyl] 6-methoxy-1,2,4-benzothiadiazine-l,l-dioxide, obtained in Example 19, is reduced withlithium aluminum hydride and aluminum chloride to yield the product3-benzyl-4-[2-piperidino- 13 ethyl] 6methoxy-3,4-dihydrol,2,4benzothiadiazine- 1 l-dioxide.

The corresponding 7-sulfamyl derivative is readily prepared inaccordance with the procedure of Example 3(D) by chloro sulfonation andthen ammoniation of the thus obtained 7-sulfonyl chloride derivative.

EXAMPLE 21 4- [3- (4-ll/lethylpipemzino)Propyl] -3-Benzylmercapto-6-Mcsyl-l ,Z,4-Benztl2iadiazine-1, I Dioxide Reaction of 25.0 g. of4-mesyl-2-amino benzenesulfonamide with 60 g. of triethylorthobenzylmercaptopropionate prepared by reacting the adduct ofbenzylmercaptan to acrylonitrile, i.e., benzylmercaptopropionitrile,with ethanolic hydrogen chloride at 7 C. to yield the imido esterhydrochloride which is converted to triethylorthobenzylmercaptopropionate in accordance with the procedure outlinedin Example 15(A) yields 6-mesyl-3- benzylmercaptoethyll,2,4-benzothiadiazinel,l-dioxide. Reaction of 10 g. of the latter with9.7 g. of N' methylpiperazinopropylchloride 2.2 g. of sodamide inaccordance with the procedure of Example (8) yields the product3-benzylmercaptoethyl 4 [3 (4 methylpiperazino)propylj 6 mesyl 1,2,4benzothiadiazinedddioxide.

The corresponding 7-sulfamyl derivative is readily prepared inaccordance with the procedure of Example 3(D) by the chlorosulfonationthereof and then ammoniation of the thus obtained 7-sulfonylchloridederivative.

EXAMPLE 22 4-[3-(4-Methylpiperazino)Propyl] 3 Benzylmercaptoethyl 6Mesyl-3,4-Dlhydr0-1,2,4-Benzothiadiazine- Ll-Dioxide The 3benzylmercaptoethyl -4 [3-(4-rnethylpiperazino)propyl] 6 mesyl 1,2,4benzothiadiazine 1,1- dioxide obtained in Example 21 is reduced withlithium aluminum hydride and aluminum chloride to yield the desiredproduct, 3-benzylmercaptoethyl-4-[3-(4-methylpiperazino)propyl] 6 mesyl3,4 dihydro 1,2,4- benzothiadiazine-1,1-dioxide.

The corresponding 7-sulfamyl derivative is readily prc pared inaccordance with the procedure of Example 3 (D) by the chlorosulfonationthereof and then ammoniation of the thus obtained 7-sulfonylchloridederivative.

EXAMPLE 23 6-Plie'noxymell1yl 3Dichl0romezhyl-4-[3-(4-Hydr0xyethylpiperazinol) Propyl] 1,2,4Benzotlziadiazine- Ll-Dioxide A mixture of 26.4 g. of4-phenoxy-2-amin'obenzenesulfonamide and 24 g. of dichloroaceticanhydride are heated for about three hours in an oil bath at 150; thetemperature is then raised to 225 and kept there for one hour to give6-phenoxymetl1yl-3-dichl0rornethyl-l,2,4- benzothiadiazine-1,l-dioxide.Reaction of 3.58 g. of the latter with 2.5 g. of3-(4-hydroxyethylpiperazino)propylchloride (prepared by the reaction ofpiperazinoethanol with trimethylene chlorobromide in an inert solvent),and 0.47 g. of sodamide in accordance with the procedure of Example15(B) yields the product 3-dichloromethyl- 4 [3 (4hydroxyethylpiperazino)propylJ--phenoxymethyl-l,2,4-benzothiadiazine-1,1-dioxide.

The corresponding 7-sulfamyl derivative is readily prepared inaccordance with the procedure of Example 3(D) by chlorosnlfonylation,and then ammoniation of the thus obtained 7-sulfonylchloride derivative.

EXAMPLE 24 6-Pl1en0xymethyl-3-Dichl0r0methyl 4[3-(4'-Hydr0xyethylpiperazino)-Pr0p yl] 3,4 Dihydro 1,2,4Benzethiadiazirze-1,1-Dioxide The 3-dichloromethyl-4- [34-hydroxyethylpiperazino) propyll-6 phenoxymethyl 1,2,4 benzothiadiazine1,1-

dioxide, obtained in Example 23, is reduced with lithium aluminumhydride and aluminum chloride to yield the desired product,3-dichlorornethyl-4-[3-(4-hydroxyethylpiperazino)propyl]-6-phenoxyrnethyl-3,4dihydro 1,2,4- benzothiadiazine-l,l-dioxide.

The corresponding 7-sulfamyl derivative is readily prepared inaccordance with the procedure of Example 3(D) by chlorosulfonation, andthen ammoniation of the thus obtained 7-sulfonylchloride derivative.

EXAMPLE 25 2{3-(Dimethylamino)Propyl] 6 Trifluoromethyl 3,4-

Dihydro-I,2,4-Benzotliiadiazine 1,1 Dioxide Mnlcic Acid Salt 6.7 g. of 2[3 (dimethylamino)propyl] 6trifluoromethyl-3,4-dihydro-l,2,4-benzothiadiazine 1,1 dioxide, maleicacid salt is dissolved in 40 ml. of isopropanol and the solution treatedwith 2.5 g. of maleic acid. The mixture is heated to the boiling pointand cooled to give the maleic acid salt.

Similarly, treating the2(3-dimethylaminopropyl)-6-trifluoromethyl-l,2,4-benzothiadiazine-l,l-dioxide,according to the procedure of Example 25, gives the maleic acid salt.

EXAMPLE 26 4-{5-(N,N-Dietlzylnmino)Pentyl] 3 Fluoro 1,2,4-Benzothiadiazine-JJ -Dioxide, Hydrochloride The base, as obtained inExample 18, is dissolved in ten volumes of anhydrous ethyl ether and thecooled solution treated with one equivalent of hydrogen chloride inether. The hydrochloride is precipitated, filtered, and recrystallizedfrom isopropanol to give the pure hydrochloride.

EXAMPLE 27 4-[5-(N,N-Diethylamino)Pcmyl] 3 Methyl 6 Fluoro- 3,4 Dihydro1,2,4 Benzothiadiazine 1,1 Dioxide Hydrochloride 7.2 g. of4-[5-(N,N-diethylamino)pcntyl]-3-methyl-6-fluoro-3,4-dihydro-1,2,4-benzothiadiazine 1,1 dioxide is dissolved inten volumes of anhydrous ethyl ether and the cooled solution treatedwith one equivalent of hydrogen chloride in ether. The hydrochloride isprecipitated, filtered and recrystallized from isopropanol to give thepure hydrochloride.

This invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

l. A compound selected from the group consisting of bases of the formulawherein R is a member selected from the group consisting of hydrogen,lower alkyl, halo, halo(lower alkyl), lower alkoxy, lower alkylsulfonyl, monocyclic carbocyclic aryl (lower alkyD-sulfonyl and cyano;one R is hydrogen and the other R is a member of the group consisting ofamino (lower alkyl), lower alkylaminoflower alkyl), di(loweralkyl)-amino(lower alkyl), phenyl(lower alkyl)amino- (lower alkyl),piperidinoflower alkyl), pyrrolidino(lower alkyl), piperazino(loweralkyl), 4-(hydroxy-lower alkyl)- piperazinoflower alkyl); R" is a memberof the group consisting of hydrogen, lower alkyl, halo(lower alkyl),pheny1(lower alkyl), phenylmercaptoflower alkyl), phenoxyflower alkyl)and phenyl(lower alkyl)mercapto- (lower alkyl); and R is a member of thegroup consisting of hydrogen and sulfamyl; and non-toxic acid additionsalts of said bases.

2. 4-di[lower alkylamino( lower alkyl)]-6-halo(loweralkyl)-3,4-dihydro-1,2,4-ben2othiadiazine l,ldioxide.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA1,1-DI(O=),2,4-DI(R''-),3-R",6-R,7-R"''-1,2,4BENZOTHIADIAZOLE WHEREIN RIS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL,HALO, HALO(LOWER ALKYL), LOWER ALKOXY, LOWER ALKYL SULFONYL, MONOCYCLICCARBOCYCLIC ARYL (LOWER ALKYL)-SULFONYL AND CYANO; ONE R'' IS HYDROGENAND THE OTHER R'' IS A MEMBER OF THE GROUP CONSISTING OF AMINO (LOWERALKYL), LOWER ALKYLAMINO(LOWER ALKYL), DI(LOWER ALKYL)-AMINO(LOWERALKYL), PHENYL(LOWER ALKYL)AMINO(LOWER ALKYL), PIPERIDINO(LOWER ALKYL),PYRROLIDINO(LOWER ALKYL), PIPERAZINO(LOWER ALKYL), 4-(HYDROXY-LOWERALKYL)PIPERAZINO(LOWER ALKYL); R" IS A MEMBER OF THE GROUP CONSISTING OFHYDROGEN, LOWER ALKYL, HALO(LOWER ALKYL), PHENYL(LOWER ALKYL),PHENYLMERCAPTO(LOWER ALKYL), PHENOXY(LOWER ALKYL) AND PHENYL(LOWERALKYL)MERCAPTO(LOWER ALKYL); AND R''" IS A MEMBER OF THE GROUPCONSISTING OF HYDROGEN AND SULFAMYL; AND NON-TOXIC ACID ADDITION SALTSOF SAID BASES.